I am a bioengineer fascinated by T cell immunology, and I have expertise in single-molecule mechanical analysis, single-molecule imaging, quantum dot nanotechnology, and single-cell signaling and functional assays. My immediate career goal is to secure an independent tenure-track faculty position at a research-intensive university in the coming years, and my long-term goal is to become a leading scientist in the area of TCR recognition and signaling. Stanford University provides a superb training environment to fulfill my career goals. My primary mentor, Professor Mark Davis, is a world-leading molecular immunologist. He has mentored over 50 postdocs and half of them have moved on to tenure-track academic positions at renowned universities. My career training will be conducted under the guidance of Professor Davis as well as an Advisory Committee comprised of six Stanford professors, specifically convened to assist me in becoming an independent principle investigator. Based on my background and career goals, my training will concentrate on experimental techniques, advanced methodologies, faculty job search, multidisciplinary collaborations, laboratory management, grant application and scientific publication. Stanford provides the best possible environment for my career development through world-leading faculty, facilities and resources as well as through a broad coverage of courses, workshops, seminars, conferences and leadership. My proposed research will focus on TCR cross-reactivity. We recently found that H1N1 influenza-specific memory CD4+ cells generated by vaccination cross-react with peptides derived from three common microorganisms of the human microbiota with the fraction of cross-reactive T cells accounting for ~10% of the H1N1-reactive T cells in healthy donors (Su et al., 2013, Immunity). Thus TCR cross-reactivity to environmental antigens could be a major mechanism in eliciting populations of memory T cells for foreign antigens that an individual has not yet encountered. Understanding TCR cross-reactivity is of critical importance in fundamental T cell immunology as well as vaccine development and immunotherapy against infectious diseases. My hypothesis is that the cross-reactivity of the TCR correlates to the binding kinetics of the TCR-pMHC interaction. This is an important question with far-reaching clinical applications, but progress has been limited due to formidable technological challenges since T cell recognition occurs over a wide time-scale ranging from milliseconds to hours and involves dynamic surface molecular interactions and complex cellular signaling and functional regulation. I am proposing to tackle this problem using my state-of- the-art approaches, including single-molecule analysis and single-cell assays as well as the powerful technologies and abundant resources available in our laboratory at Stanford. I will perform a comprehensive investigation on the TCR cross-reactivity at the single-molecule and single-cell level, covering recognition specificity, sensitivity, and kinetics. The knowledge gaine from this study will not only provide indispensable new insights into the immune function of the abundant human memory cells, but also will advance the development of novel vaccines and benefit the prevention and treatment of infectious diseases.